At its January meeting, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has issued a positive recommendation for the marketing authorization of Kygevvi (doxecitine and doxribtimine, UCB Pharma) for treating thymidine kinase 2 deficiency (TK2d).

This recommendation, if followed by the European Commission’s approval, would make Kygevvi the first therapy authorized in the European Union specifically for TK2d, an ultra-rare, life-threatening genetic mitochondrial disorder characterized by progressive muscle wasting and respiratory failure.

The positive CHMP opinion covers both pediatric and adult patients whose disease symptoms began by age 12.

Kygevvi received regulatory support through EMA’s Priority Medicines (PRIME) scheme, which provides enhanced scientific and regulatory guidance for medicines addressing significant unmet needs. The therapy was granted PRIME eligibility in June 2018.

Disease Background and Current Management

TK2 deficiency is a rare genetic disorder affecting fewer than 1 in 1,000,000 people and represents a rare, life-threatening genetic disorder with no previously authorized therapy in Europe. Worldwide clinical experience has been limited, and until now there have been no disease-modifying treatments approved anywhere to address the underlying cause beyond supportive care.

The condition is caused by mutations in the TK2 gene, which impair the TK2 enzyme’s ability to maintain mitochondrial DNA. This dysfunction prevents muscles from generating adequate energy, resulting in progressive myopathy, motor function decline, loss of ambulation, respiratory difficulties, and reduced life expectancy.

Clinical management to date has been limited to supportive care, including nutritional support via feeding tubes, physiotherapy for mobility, and ventilatory support for respiratory compromise.

Restoring Mitochondrial DNA Integrity

Kygevvi contains two active substances, doxecitine and doxribtimine, which are pyrimidine nucleosides. Although the precise mechanism in humans remains under investigation, animal studies suggest these compounds are modified and incorporated into mitochondrial DNA within muscle cells, improving mitochondrial DNA production and maintenance. This process is expected to compensate for reduced TK2 enzyme activity and slow disease progression.

Reversing Motor Decline

The recommendation relied on data from a retrospective chart review study (MT-1621-101) and a phase 2 single-arm clinical study (TKO102), involving 39 patients with TK2d whose disease onset occurred by age 12. The effect of the therapy on motor function was assessed by comparing motor milestones before and after therapy in each patient. Findings demonstrated that 84% of patients regained one or more motor milestones following Kygevvi therapy, indicating the medicine improves motor function. The benefit of Kygevvi includes a reduction in the number of motor milestones lost or even regaining motor milestones, as observed in the pooled analysis.

Safety Profile and Administration

The most frequent adverse events were gastrointestinal, including diarrhea, vomiting, and abdominal pain. 

The therapy will be available as a 2 g/2 g powder for oral solution and must be administered under the supervision of specialists experienced in mitochondrial disorders.

Regulatory Pathway and Access

The marketing authorization was recommended under exceptional circumstances — a pathway reserved for conditions where comprehensive efficacy and safety data cannot be provided due to extreme rarity. This authorization carries specific post-approval obligations that undergo annual review. The EMA has required UCB Pharma SA (Belgium), the marketing authorization applicant, to conduct an additional study to further confirm Kygevvi’s safety and efficacy.

The therapy was designated an orphan medicinal product for mitochondrial DNA depletion syndrome (myopathic form) on 20 April 2017. Following the positive CHMP opinion, the Committee for Orphan Medicinal Products will assess whether this designation should be maintained.

The CHMP opinion represents an intermediary step toward patient access. The opinion will now be sent to the European Commission for adoption of a decision on EU-wide marketing authorization. Once marketing authorization is granted, price and reimbursement decisions will occur at individual member state levels.

Detailed recommendations for product use will be described in the Summary of Product Characteristics, which will be published on the EMA website in all official EU languages after the European Commission grants marketing authorization.